Neuroanatomy and Physiology ... in Substance Abuse

How does experimental use of substances of abuse lead to drug addiction in some individuals? How do these drugs cause intoxication? Part of the answer lies in a common reinforcement pathway in the human brain which drugs of abuse stimulate, potentially leading to addiction (1,2,3,4,7). This reinforcement pathway, which is composed of both central nervous system structures and endogenous neurotransmitters communicating between these structures, has been termed the “reward pathway”(1). The reward pathway evolved to promote activities that are essential to the survival of the human race as well as other mammals.

One may compare the mechanism of drugs of abuse with that of viruses. Viruses and drugs of abuse are both foreign to humans. Viruses enter an animal’s cells and use the pre-existing cell “machinery” to synthesize more viruses, thus promoting their own survival. As the viruses infect more and more cells, the organism may become ill. Illicit drugs can take advantage of an organism in a similar fashion. Just as viruses take over cell function throughout the body, drugs of abuse modify cell function in these important brain structures leading to modifications in behavior. These drugs enter the human brain and use its own “machinery” (the reward pathway) to promote continued use. Just as the cell’s survival is dependent on its “machinery” so is the survival of the organism dependent on an intact brain reward pathway. Drugs of abuse, although harmful to the organism, are able to capture this “machinery “ in some individuals driving further drug use.

Depending on our own characteristics (our inherited neurochemical make-up etc.) we may be more susceptible to the illness of drug addiction just as certain people are more susceptible to infection. Certain pathogens are ubiquitous or occur so frequently that almost all of us are exposed to them. Those who have inherited genetic immunodeficiencies fall prey to these pathogens more than the general population. Similarly, individuals who have a genetic predisposition, may be more vulnerable to addiction after exposure to the drug.

As noted earlier, substances of abuse affect the brain reward pathway, which is made of neurons that release chemicals when they are stimulated. This release leads to subjective feelings of well being (1,2). This brain reward system evolved to subserve activities essential to species survival, such as sexual activity and feeding behaviors. Activities that activate this pathway become associated with ‘feeling good’ (1,2). For example, sexual intercourse causes release of chemicals activating this pathway, and the result is a feeling of well being. Thus, the reward pathway serves to promote survival of the species by rewarding behaviors necessary for continued survival (seeking food, reproduction, shelter, drink, etc). Drugs of abuse stimulate this “brain reward” pathway in a similar fashion, and this is why substance users experience feelings of pleasure or “high” when they use them (1,2). When drugs of abuse are repeatedly used, they may “commandeer” the brain reward system, driving compulsory drug use to the exclusion of other adaptive activities. Thus, “addiction” can be partially explained by the action of drugs of abuse on this common reward pathway, in which drug use stimulates further use and drug seeking behavior (1,2,3,4).

In the following paragraphs, the basic anatomy of the reward pathway and brain structures that interact with this pathway will be discussed. Next, the molecular physiology of the reward pathway will be delineated. After laying the foundation of the anatomy and physiology of brain reward, the specific interactions of drugs of abuse will be examined. Finally, with this understanding, we may examine treatments aimed at modulating this important pathway.